Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019158 (hepatitis)
 30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatitis C virus (HCV) is the major causative agent of non-A non-B hepatitis, an important health problem with an estimated 50 million people infected worldwide. Among the possible targets for therapeutic intervention, the serine protease contained within the N-terminal region of nonstructural protein 3 (NS3 protease) is so far the best characterized. In vitro characterization of synthetic substrates based on all the natural cleavage sites (as well as a series of analogs) has consistently revealed poor kinetic parameters, making them unsuitable for sensitive high-throughput screening. To overcome these difficulties, we have recently developed depsipeptide substrates incorporating an ester bond between residues P1 and P&prime1. Due to ready transesterification of the scissile bond to the acyl-enzyme intermediate, these substrates showed very high kcat/Km values, enabling detection of activity with subnanomolar NS3 concentrations. We have used the same principle to synthesize internally quenched depsipeptide fluorogenic substrates based on resonance energy transfer between the donor/acceptor couple 5-[(2'-aminoethyl)amino]naphthalene sulfonic acid/4-[[4'-(dimethylamino)phenyl]azo]benzoic acid, and developed a continuous assay for NS3 activity. Substrate cleavage is linear with enzyme concentration: depending on the conditions chosen, we estimated a detection limit for NS3 between 1 nM and 250 pM. The suitability of the assay for evaluation of inhibitors was established using as competitor a tridecapeptide corresponding to the natural NS4A/4B cleavage site; this gave an IC50 of 30 microM, well in agreement with the previously found Km value (40 microM).
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PMID:A continuous assay of hepatitis C virus protease based on resonance energy transfer depsipeptide substrates. 881 80

Hepatitis C virus (HCV) is the major etiological agent of posttransfusion and community-acquired non-A, non-B hepatitis. It is an enveloped virus, grouped as a separate genus in the Flaviviridae family. The plus-stranded RNA genome encodes a polyprotein of about 3000 amino acids with the structural proteins core, E1 and E2 residing in the amino terminal quarter of the polyprotein and the nonstructural proteins NS2, NS3, NS4A, NS4B, NS5A and NS5B in the remainder. Maturation of the structural proteins is mediated by host cell signalases located in the lumen of the endoplasmic reticulum and cleaving behind stretches of hydrophobic amino acids. At least two virally encoded proteinases are responsible for processing of the NS proteins: a zinc-dependent metallo-proteinase encompassing the NS2 domain and the amino terminal portion of NS3, which is essential for cleavage at the NS2/3 junction; a serine-type proteinase located in the amino terminal domain of NS3 is required for cleavage at all sites downstream of the NS3 carboxy terminus. However, although the NS3 domain contains proteolytic activity, with the exception of the NS5A/5B junction cleavage only occurs in the presence of NS4A. This 54 amino acid long peptide can modulate the proteolytic activity of the enzyme in cis and in trans, probably by the formation of a stable NS3/NS4A complex. Modulation of the proteinase activity may be a way to regulate the expression and replication of the HCV genome.
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PMID:Processing pathways of the hepatitis C virus proteins. 883 84

The NS3 protein of hepatitis C virus contains a chymotrypsin-like serine proteinase domain. We built a homology model of this domain which predicts the presence of a tetradentate metal binding site formed by three cysteines and one histidine. These residues are strictly conserved in all known hepatitis C viral genotypes as well as in other recently discovered related hepatitis viruses. We show that the hepatitis C virus enzyme does indeed contain a Zn2+ ion with S3N ligation and that the metal is required for structural integrity and activity of the enzyme. Strikingly, the residues forming the metal binding site are also conserved in the chymotrypsin-like 2A cysteine proteinases of picornaviruses. Remarkably, in these highly variable viral genomes the metal binding site is more conserved than the catalytic residues and thus allows us to define a novel class of zinc binding chymotrypsin-like proteinases and to identify a new attractive target for antiviral therapy.
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PMID:A zinc binding site in viral serine proteinases. 887 93

Hepatitis C virus (HCV) is the major etiologic agent of non-A, non-B hepatitis. One of the difficulties in developing anti-HCV drugs is the lack of an efficient HCV cultivation system. We have generated an artificial surrogate virus suitable for testing the antiviral effects of drugs affecting HCV protease NS3, an enzyme believed to be essential for HCV proliferation. The surrogate virus genome is composed of most of the poliovirus genome and HCV protease NS3 and an NS3-specific cleavage site. The activity of HCV protease NS3 is required for proliferation of this chimeric virus. The antiviral efficacy of HCV protease inhibitors can, therefore, be evaluated by examining the effects of the drugs on the surrogate virus proliferation.
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PMID:Generation of a novel poliovirus with a requirement of hepatitis C virus protease NS3 activity. 895 51

Recently, GBV-C and HGV-two isolates of the same new flavivirus-were identified in serum samples of patients with indeterminate hepatitis and posttransfusion hepatitis, respectively. The pathogenic relevance of these viruses is still uncertain. As viral infections are presumed to trigger autoimmune processes, we investigated GBV-C in autoimmune hepatitis as well as in cryptogenic hepatitis, and compared the prevalences to patients with chronic viral hepatitis and those of blood donors. We found only a slightly higher prevalence of the virus in cryptogenic (12%) and autoimmune hepatitis type I-III (6.7%, 10%, and 12.5%) compared to blood donors (4.7%). In contrast, patients with viral hepatitis B, C, and D were more frequently infected with GBV-C (16%, 20%, 36%). These results suggest that GBV-C is not a major cause for inducing autoimmunity and leading to autoimmune hepatitis. We analyzed the nucleic acid sequences of a representative number of GBV-C positive patients (24/42) and found a broad range of nucleotide similarity in the NS3 helicase region (74-100%) among the isolates and the prototype sequences. However, we could not identify a specific sequence, which would point to a certain strain or subtype of the virus associated with autoimmune or cryptogenic liver disease.
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PMID:GBV-C/HGV is not the major cause of autoimmune hepatitis. 900 30

In 1995, a new human hepatitis virus belonging to the family Flaviviridae was described and designated hepatitis GBV-C. To investigate variations within the genome of GBV-C and to study the relationship of GBV-C to GBV-A/B or hepatitis C virus (HCV), we established a detection system using reverse transcriptase polymerase chain reaction (RT-PCR) of the putative helicase region (NS3). So far, isolates derived from 14 different GBV-C-positive sera were analyzed (GBV-C/S3-36), showing 80.1-89.4% (mean: 85%) identical nucleotides. The deduced amino acid sequences revealed 97.3% homology. Nucleotide sequences of GBV-C/S3-36 revealed about 60% identity to GBV-A as well as to HCV, but only 56% identity to GBV-B. Amino acid sequences revealed 73.4 and 68.6% similarity to GBV-A and GBV-B, respectively, but a slightly higher percentage of 78.5% to HCV sequences. Thus, according to the putative GBV-C helicase sequence, a subtyping of GBV-C into different genotypes may be necessary.
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PMID:Sequence analysis of hepatitis GB virus C (GBV-C) isolates from 14 patients. 902 80

In a significant number of cases of fulminant (presumed viral) hepatitis worldwide, no aetiological agent has been identified. Recently, it has been suggested that a newly described flavivirus, GBV-C, is responsible for some of these cases. This study aimed to assess the clinical significance of GBV-C RNA, demonstrated by reverse transcriptase-polymerase chain reaction (RT-PCR), in the serum of patients with fulminant non-A to E hepatitis. Twenty-three consecutive cases of non-A to E fulminant hepatitis were included in the study. GBV-C RNA was reverse transcribed and amplified using two RT-PCR based detection methods. Medical records were examined to assess clinical history, duration and mode of infection, transfusion history, liver histology and clinical outcome. Five (three female, two male; mean age 21.2 years) of 23 patients had GBV-C RNA detected in their serum by RT-PCR: all five patients were RT-PCR positive following amplification by primers specific for the 5' non-coding region (NCR), whilst four were positive by primers for the NS3 region. Prior to the onset of illness, two patients had risk factors for transmission of an infectious agent; however, all five patients had been transfused during their illness, prior to testing for GBV-C. Of these, two (of two in whom serum was available) were negative for GBV-C after the onset of fulminant hepatitis but before their first transfusion. This study does not support the hypothesis that the detection of hepatitis G virus (HGV)/GBV-C RNA in the serum of patients with fulminant hepatitis indicates a causal association. However, it does demonstrate that a careful transfusion history and screening of blood products is vital before the importance of GBV-C in the aetiology of fulminant hepatitis can be established.
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PMID:The clinical significance of the detection of hepatitis GBV-C RNA in the serum of patients with fulminant, presumed viral, hepatitis. 903 Oct 64

We tested HGV RNA in serum in addition to HBV DNA and HCV RNA to study the causative agents involved in chronic non-B, non-C hepatitis. Twenty five patients diagnosed as having chronic non-B, non-C hepatitis(negative for HBsAg and HCV-Ab), were investigated in this study. HGV RNA was detected by nested RT-PCR using primers in 5'-untranslated, NS3 and NS5 regions. Of the 25 patients, 4(16%) were positive for HGV RNA, only 1(4%) was positive for HBV DNA and none were positive for HCV RNA. Of the 4 patients with HGV RNA, 2 histologically has mild fibrosis and the remaining 2 had cirrhosis. One patient with cirrhosis also had hepatocellular carcinoma; HBV DNA was positive in this patient. All 3 patients with only the HGV infection had a mild histological grade. In conclusion, HGV infection was involved in 16% of Japanese patients with chronic non-B, non-C hepatitis. Chronic hepatitis G seemed to exhibit mild hepatitis activity.
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PMID:[GB virus C/hepatitis G virus infection in patients with chronic non-B, non-C hepatitis]. 908 58

In previous studies, human hepatitis viruses have been experimentally transmitted to New World monkeys of the genus Saguinus (tamarins). Recently, two Flaviviridae-like agents (GBV-A and GBV-B) were identified in tamarins that developed hepatitis following inoculation with serum of the 11th tamarin passage of a potentially new human hepatitis agent. However, it was not shown that these viruses originated from the initial inoculum. We here report the discovery of indigenous species-specific viruses related to GBV-A in several species of New World monkeys and suggest that GBV-A virus was fortuitously acquired during passage in tamarins. Sera or plasma from 98 wild-caught New World monkeys representing 10 different species was tested by RT-PCR with conserved degenerate primers to the 5' noncoding region of the genome. Viral sequences were identified in 33 animals and sequence analysis was performed on the amplicons. In addition, the genomic region corresponding to the putative NS3 RNA helicase of GBV-A was amplified from most positive animals and sequenced. We detected GBV-A-like viruses in 13 (35%) of 37 S. mystax, 7 (78%) of 9 S. nigricollis, 3 (25%) of 12 S. labiatus, 2 (50%) of 4 S. oedipus, 2 (100%) of 2 Callithrix jacchus, and 6 (50%) of 12 Aotus trivirgatus monkeys. Each positive animal was infected with a unique strain of the GBV-A-like viruses. Analysis of the 5' NC and NS3 helicase sequences revealed that these viruses could be classified into 5 major genetic groups with genetic distances equivalent to or greater than those found among major genetic groups of hepatitis C virus. Species-specific GBV-A-like viruses were found in S. mystax, S. nigricollis, S. oedipus, C. jacchus, and A. trivirgatus species. The viruses specific for S. nigricollis were closely related to GBV-A, suggesting that GBV-A was acquired by passage through this species during the initial transmission studies. The natural history of the GBV-A-like viruses was studied in serial serum samples from 9 S. mystax and 2 A. trivirgatus monkeys. Each animal was chronically infected and the viral strain did not vary during 9-27 months of follow-up. Finally, we demonstrated that four S. mystax were positive upon arrival to the United States from the country of origin. No apparent disease was associated with chronic infection of the GBV-A-like viruses. In conclusion, many New World monkeys are persistently infected with indigenous species-specific viruses that may represent a new genus within the virus family Flaviviridae.
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PMID:Five new or recently discovered (GBV-A) virus species are indigenous to New World monkeys and may constitute a separate genus of the Flaviviridae. 912 55

Prevalence of hepatitis G virus (HGV) was determined in a cohort of Chinese blood donors and hepatitis patients by the detection of viral RNA via reverse transcription-polymerase chain reaction. While HGV RNA was detected in only 1 of 150 healthy volunteers, the detection rate among professional blood donors was surprisingly high (21/265, 7.9%), and plasmapheresis was identified as a significant risk factor in this population. It was also shown that an elevated serum alanine aminotransferase level is not a reliable marker for HGV infection. Prevalences of HGV in patients with hepatitis C, with non-A-E hepatitis, and with hepatocellular carcinoma were relatively low (8.2%, 16.7%, and 6.1%, respectively). Striking sequence homology (>90%) shared by 5 HGV cDNA clones implicated that they belonged to the same genotype. Phylogenetic analysis of a 446-bp NS3 cDNA confirmed that this genotype was closely related to the prototype viruses.
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PMID:Prevalence and genotype of hepatitis G virus in Chinese professional blood donors and hepatitis patients. 912 92


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